Impact of age and prior COVID-19 on the response to influenza a components in the 2020–2021 Fluzone vaccine

Understanding how age and prior COVID-19 infection influenced influenza vaccine responses during the early SARS-CoV-2 pandemic is important for identifying factors that affect vaccine efficacy and for optimizing immunization strategies in diverse populations amid co-circulating respiratory viruses. In this study, participants were enrolled during the 2020-2021 season to receive the Fluzone vaccine, and their humoral responses to the influenza A components were analyzed in relation to age and COVID-19 history. Anti-H1 hemagglutinin (HA) responses were assessed at baseline and multiple time points post-vaccination using neutralizing antibody assays against a contemporary H1-expressing pseudovirus, measurements of H1 HA-specific memory B cells, and profiling of anti-H1 IgG glycosylation. Anti-H3 antibody responses were evaluated using a hemagglutination inhibition (HI) assay. While prior COVID-19 infection was not associated with notable differences in the humoral response in this cohort, older age consistently correlated with reduced responses across multiple readouts. These findings highlight the need for targeted approaches to improve influenza vaccine effectiveness in older adults, who remain at elevated risk for severe outcomes from both influenza virus and SARS-CoV-2 infections.